Role of endothelin-A receptors in ischemic contracture and reperfusion injury.
BACKGROUND
Circulating endothelin (ET)-1 is elevated in ischemia/reperfusion and may exert proischemic effects. The aim of the present study was to characterize the effects of ET-1 in rat isolated hearts using subtype-selective ET receptor antagonists, agents modulating the cytosolic Ca2+ concentration, or the activity of cGMP-dependent protein kinase.


RESULTS
Rat hearts perfused at constant pressure were made ischemic by reducing flow to 0.2 mL x min(-1) x g(-1), followed by reperfusion at normal pressure (each phase, 25 minutes). Drugs were infused during the ischemic phase only. Parameters monitored were extent and time-to-onset of contracture in ischemia, left ventricular developed pressure (LVDevP), coronary flow (CF), and diastolic relaxation during reperfusion. The ET(A) receptor-selective antagonist PD 155080 (50 nmol/L) reduced peak ischemic contracture (-49%) and delayed its time to onset (+56%) and improved recovery of reperfusion LVDevP (+12%), CF (+16%), and diastolic relaxation (+50%). Infusion of an ET(A)/ET(B)-nonselective antagonist, PD 142893 (200 nmol/L), had similar effects on all parameters, whereas infusion of BQ-788 (20 nmol/L), an ET(B) receptor-selective antagonist, was without effect. Exogenous ET-1 (100 pmol/L) hastened contracture and increased its extent (+23%) and reduced recovery of both LVDevP (-31%) and CF (-18%), effects that were counteracted by HOE 642 (10 micromol/L), a Na+/H+ exchange inhibitor, but not by nicardipine (30 micromol/L), a Ca2+ entry blocker; activation of cGMP-dependent protein kinase by the cell-permeable cGMP analog Sp-8-p-chlorophenylthioguanosine-3',5'-cyclic monophosphorothioate (10 micromol/L) improved function without preventing the effects of ET-1.


CONCLUSIONS
The data indicate that ET-1 exacerbates ischemic contracture and worsens ventricular and coronary reperfusion dysfunction by activating ET(A) receptors via a mechanism likely involving activation of Na+/H- exchange in this model.
Brunner
F
F
Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Austria. friedrich.brunner@kfunigraz.ac.at
Opie
L H
LH
D000818:Animals; D003331:Coronary Vessels / Q000503:physiopathology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*
D019332:Endothelin-1; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D017869:Cyclic GMP-Dependent Protein Kinases